[unreadable] This application proposes to develop imaging agents targeting beta-amyloid (Abeta) plaques in the brain of patients with Alzheimer's disease (AD). Cognitive decline and behavioral changes related to old age and AD are often very difficult to differentiate. This is an important clinical question with high impact to millions of potential AD patients. Currently, there is no simple and definitive imaging tool available to assist the diagnosis. Recent reports suggest that accelerated accumulation of Abeta plaques in the brain may be a key risk factor associated with AD. Therefore, Abeta plaques in the brain could be useful as a biomarker for differential diagnosis of AD. Imaging the key component, Abeta protein aggregates, may provide pivotal information pertinent to the initiation and progression of AD. A series of F-18 labeled agents with high binding affinity towards Abeta plaques are proposed as positron emission computed tomography (PET) imaging agents. They are potentially useful to directly estimate the Abeta burden relevant to pathological states of AD and evaluate effects of potential therapeutic drugs aimed at reducing the plaques. Five specific aims are proposed: 1) novel candidates with potential of showing high binding affinity towards Abeta aggregates will be synthesized, 2) binding affinity of proposed candidates will be measured with preformed Abeta aggregates, 3) after optimizing the binding affinity selected candidates will be labeled with F-18, 4) in vivo biodistribution in normal mice after an intravenous injection of a F-18 labeled tracer will be performed to investigate the brain penetration. Additional biodistribution studies of promising agents will also be evaluated in a transgenic animal model of AD and normal non-human primates to assess species differences. The transgenic mice specially engineered to produce excess Abeta plaques in the brain will be injected with selected F- 18 imaging agents. Labeling of Abeta plaques in the cortex and hippocampus regions in the living brain of transgenic mice will be confirmed by ex vivo autoradiography, 5) PET imaging studies of these mice with an animal PET scanner will be performed to select final candidates suitable for phase I clinical trial as biomarkers for diagnosis of Alzheimer's disease. [unreadable] [unreadable]